US9453006B2 - Crystalline form having specific crystal habit and pharmaceutical composition containing this crystalline form as active ingredient - Google Patents
Crystalline form having specific crystal habit and pharmaceutical composition containing this crystalline form as active ingredient Download PDFInfo
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- US9453006B2 US9453006B2 US14/388,218 US201314388218A US9453006B2 US 9453006 B2 US9453006 B2 US 9453006B2 US 201314388218 A US201314388218 A US 201314388218A US 9453006 B2 US9453006 B2 US 9453006B2
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- luliconazole
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- 239000013078 crystal Substances 0.000 title claims abstract description 189
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 22
- 239000004480 active ingredient Substances 0.000 title description 5
- YTAOBBFIOAEMLL-REQDGWNSSA-N Luliconazole Chemical compound ClC1=CC(Cl)=CC=C1[C@H](CS\1)SC/1=C(\C#N)N1C=NC=C1 YTAOBBFIOAEMLL-REQDGWNSSA-N 0.000 claims abstract description 52
- 229960000570 luliconazole Drugs 0.000 claims abstract description 47
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 24
- 230000005855 radiation Effects 0.000 claims abstract description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 38
- 238000000034 method Methods 0.000 claims description 13
- 230000001954 sterilising effect Effects 0.000 claims description 13
- 239000008186 active pharmaceutical agent Substances 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- 206010046914 Vaginal infection Diseases 0.000 claims description 9
- 239000011148 porous material Substances 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 201000008100 Vaginitis Diseases 0.000 claims description 6
- 206010035664 Pneumonia Diseases 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 125000004434 sulfur atom Chemical group 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- 230000000694 effects Effects 0.000 description 17
- 241000224526 Trichomonas Species 0.000 description 15
- 238000001914 filtration Methods 0.000 description 14
- 238000005259 measurement Methods 0.000 description 13
- 238000012982 x-ray structure analysis Methods 0.000 description 12
- 239000003814 drug Substances 0.000 description 11
- 201000010099 disease Diseases 0.000 description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 9
- 239000000825 pharmaceutical preparation Substances 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 8
- 238000001953 recrystallisation Methods 0.000 description 8
- 208000002474 Tinea Diseases 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 241000233866 Fungi Species 0.000 description 6
- 201000004647 tinea pedis Diseases 0.000 description 6
- 206010067409 Trichophytosis Diseases 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 239000002504 physiological saline solution Substances 0.000 description 5
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 4
- 208000007163 Dermatomycoses Diseases 0.000 description 4
- 241001313288 Labia Species 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 201000003929 dermatomycosis Diseases 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 208000010195 Onychomycosis Diseases 0.000 description 3
- 229940121375 antifungal agent Drugs 0.000 description 3
- 239000003429 antifungal agent Substances 0.000 description 3
- -1 benzenesulfonyloxy group Chemical group 0.000 description 3
- 238000007664 blowing Methods 0.000 description 3
- 230000006866 deterioration Effects 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000004659 sterilization and disinfection Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 201000005882 tinea unguium Diseases 0.000 description 3
- 206010005913 Body tinea Diseases 0.000 description 2
- 241000222122 Candida albicans Species 0.000 description 2
- 206010007134 Candida infections Diseases 0.000 description 2
- 208000003322 Coinfection Diseases 0.000 description 2
- 102000011782 Keratins Human genes 0.000 description 2
- 108010076876 Keratins Proteins 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 235000010724 Wisteria floribunda Nutrition 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 201000003984 candidiasis Diseases 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000000717 retained effect Effects 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 230000036962 time dependent Effects 0.000 description 2
- 201000003875 tinea corporis Diseases 0.000 description 2
- 230000000007 visual effect Effects 0.000 description 2
- 0 *C1=CC=C(C([Y])CC)C(C)=C1.*C1=CC=C(C2CS/C(=C(/C#N)N3C=CN=C3)S2)C(C)=C1.II.I[IH]I.I[IH]I.N#CC(=C(CS)CS)N1C=CN=C1.N#CC(=C(CS)CS)N1C=CN=C1.N#CCN1C=CN=C1.S=C=S Chemical compound *C1=CC=C(C([Y])CC)C(C)=C1.*C1=CC=C(C2CS/C(=C(/C#N)N3C=CN=C3)S2)C(C)=C1.II.I[IH]I.I[IH]I.N#CC(=C(CS)CS)N1C=CN=C1.N#CC(=C(CS)CS)N1C=CN=C1.N#CCN1C=CN=C1.S=C=S 0.000 description 1
- ZPGCVVBPGQJSPX-UHFFFAOYSA-N 2-imidazol-1-ylacetonitrile Chemical compound N#CCN1C=CN=C1 ZPGCVVBPGQJSPX-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 206010017533 Fungal infection Diseases 0.000 description 1
- 208000031888 Mycoses Diseases 0.000 description 1
- 208000035415 Reinfection Diseases 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 208000007712 Tinea Versicolor Diseases 0.000 description 1
- 206010056131 Tinea versicolour Diseases 0.000 description 1
- 208000005448 Trichomonas Infections Diseases 0.000 description 1
- 241000224527 Trichomonas vaginalis Species 0.000 description 1
- 206010044620 Trichomoniasis Diseases 0.000 description 1
- 241000223238 Trichophyton Species 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000000842 anti-protozoal effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000003716 antitrichomonal agent Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- DNTGGZPQPQTDQF-XBXARRHUSA-N crotamiton Chemical compound C/C=C/C(=O)N(CC)C1=CC=CC=C1C DNTGGZPQPQTDQF-XBXARRHUSA-N 0.000 description 1
- 229960003338 crotamiton Drugs 0.000 description 1
- 238000000151 deposition Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 229940124508 injectable medicine Drugs 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 125000005948 methanesulfonyloxy group Chemical group 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 238000000373 single-crystal X-ray diffraction data Methods 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000003696 structure analysis method Methods 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- BWMISRWJRUSYEX-SZKNIZGXSA-N terbinafine hydrochloride Chemical compound Cl.C1=CC=C2C(CN(C\C=C\C#CC(C)(C)C)C)=CC=CC2=C1 BWMISRWJRUSYEX-SZKNIZGXSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 239000000003 vaginal tablet Substances 0.000 description 1
- 229940044977 vaginal tablet Drugs 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Definitions
- the present invention relates to a crystal having a crystal habit of luliconazole which is useful as an active pharmaceutical ingredient, and a pharmaceutical composition which contains the crystal as the active pharmaceutical ingredient.
- Luliconazole is an antifungal agent which is excellent in the action on fungi.
- luliconazole is widely used as a pharmaceutical or medicine for tinea pedis and tinea corporis , and it is going to be applied for the action on tinea unguium .
- problems which should be solved, for example, that luliconazole is converted to the stereoisomers such as the SE isomer and the Z isomer, and the crystallization of luliconazole is caused immediately after the application (see, for example, Patent Documents 1 to 6).
- luliconazole is to be applied to pneumonia and vaginitis (colpitis), without being limited to Trichophyton , because luliconazole has a strong antifungal action.
- luliconazole also has an antiprotozoal effect on Trichomonas which may coexist highly probably. Therefore, it is affirmed that luliconazole is desired to be applied thereto as compared with any other antifungal agent.
- the oral administration or the administration by injection is usually adopted as the administration route thereof. In the case of the administration by injection, the problem of solubilization (solubility) solemnly exists. In other words, it is affirmed that any means to improve the solubility of luliconazole has been desired to be developed.
- the present invention has been made in the circumstances as described above, an object of which is to provide means for improving the solubility of luliconazole.
- the phrase “excellent in solubility”, which is referred to in the present invention, does not mean such a state that the state seems to be a solubilized state by being viewed by naked eyes but fine or minute crystals, which cannot be sensed by naked eyes, are present in a dispersed manner, but the phrase means such a state that any crystal, which may be lost by filtration, is absent even when the filtration is performed by using a filter having a pore size of 0.2 to 0.4 ⁇ m.
- the present invention has the following features.
- a crystal of luliconazole represented by the following formula, wherein the crystal has such a crystal habit that (011) plane is a specific crystal growth plane:
- a method for producing a pharmaceutical composition comprising a step of dissolving, in a solvent, the crystal as defined in any one of (1) to (5) or the active pharmaceutical ingredient as defined in (6), followed by being filtrated through a sterilizing filter (sterilization filter).
- the sterilizing filter is a filter which has a pore size of 0.2 ⁇ m to 0.5 ⁇ m.
- FIG. 1 shows results of the powder X-ray diffraction measurements performed for Crystal 1 of Example 1, Crystal 2 of Example 2, and a crystal having such a crystal habit that the (11-1) plane is a specific crystal growth plane.
- FIG. 2 shows the packing diagram (halftone image) obtained by single crystal X-ray diffraction data of luliconazole for Crystal 1 of Example 1.
- the atom affixed with a symbol S is the sulfur atom.
- the crystal of luliconazole of the present invention is characterized in that the crystal has such a crystal habit that (011) plane is a specific crystal growth plane.
- the crystal having the crystal habit as described above can be prepared by dissolving luliconazole in lower alcohol such as ethanol or the like while being heated (dissolving temperature: 60 to 70° C.), performing cooling while applying gentle stirring, adding a poor solvent such as water or the like, depositing crystals, separating the crystals by means of filtration, and drying the crystals while performing blowing at a low temperature of 30 to 40° C.
- the amount of the poor solvent to be added is a volume of 10 to 40% with respect to the lower alcohol, for the following reason.
- the (011) plane does not become the specific crystal growth plane in some cases.
- the lower alcohol it is preferable to use alcohol having a number of carbon atoms of 2 to 4. It is possible to preferably exemplify, for example, ethanol, isopropyl alcohol, and n-butanol. It is also possible to appropriately add diethyl ether and/or diisopropyl ether to regulate the solubility.
- Two or more alcohols, which are selected from the alcohols as described above, can be mixed and used as a solvent for recrystallization as well.
- the alcohol as described above may be used together with water when the alcohol is used, or the alcohol may be used in a state in which water is previously contained. It is preferable to adopt such a form that water is added as the poor solvent after the dissolution of the crystal.
- Recrystallization can be performed in accordance with any ordinary recrystallization technique.
- FIG. 1 shows the result of the powder X-ray diffraction measurements performed for the crystals having such a crystal habit that the (011) plane is the specific crystal growth plane.
- the crystal which has such a crystal habit that the (011) plane is the specific crystal growth plane as described above, has the crystal system which resides in the monoclinic crystal.
- the crystal which has such a crystal habit that the (11-1) plane is the specific crystal growth plane and which is obtained by recrystallizing luliconazole from a mixed solvent obtained by mixing equal amounts of ethyl acetate and normal hexane, also has the crystal system which resides in the monoclinic crystal, wherein the diffraction angle, which is obtained as a result of the powder X-ray diffraction measurement, is coincident with that of the crystal which has such a crystal habit that the (011) plane is the specific crystal growth plane.
- the diffraction intensity differs between the both. That is, it is considered that the two types of crystals described above have the same crystal form but have different crystal habits.
- the specific crystal growth plane of the crystal herein means the plane on which the growth occurs with ease as compared with other planes.
- the specific crystal growth plane is the plane which belongs to the peak that has a significantly strong intensity as compared with integrated intensities of other diffraction peaks within a measured diffraction angle range when the powder X-ray diffraction measurement is performed.
- the specific crystal growth plane of the crystal can be detected, for example, as the peak which specifically has the high diffraction intensity in the powder X-ray diffraction measurements for the crystals.
- the phrase “the value of 2 ⁇ is provided in the vicinity of 13.5°” means, for example, that 2 ⁇ is provided in a range of 13.5° ⁇ 0.7°, preferably that 2 ⁇ is provided in 13.5° ⁇ 0.5°.
- the numerical value is presented with reference to the effect of the crystal referred to in Examples described later on.
- Luliconazole which is to be used to prepare the crystal having the crystal habit as described above, can be used irrelevant to the crystal system thereof, provided that the purity thereof is not less than 90% and more preferably not less than 95%.
- Luliconazole as described above can be synthesized, for example, in accordance with a method described in Japanese Patent Application Laid-open No. 60-218387. That is, 1-(cyanomethyl)imidazole and carbon disulfide are reacted to obtain a compound of (III) which is reacted with a compound of a general formula (II) having a leaving group, and thus a compound represented by a certain general formula (1) can be obtained.
- the compound which corresponds to R ⁇ X ⁇ Cl and which is included in the compounds represented by the general formula (1), is luliconazole.
- the leaving group as described above can be preferably exemplified, for example, by methanesulfonyloxy group, benzenesulfonyloxy group, p-toluenesulfonyloxy group, or halogen atom.
- Y and Y′ represent leaving groups, and M represents alkali metal.
- the crystal which is the crystal of the present invention obtained as described above and which has such a crystal habit that the (011) plane is the specific crystal growth plane, is excellent in the solubility in alcohol, especially ethanol.
- the crystal of the present invention is excellent in the function to avoid any remaining crystal which is usually fine or minute and which cannot be sensed by naked eyes. Therefore, even when the filtration is performed by using a filter paper for sterilization having a small pore size, any slight decrease in the active ingredient, which would be otherwise caused thereby, is not observed. Therefore, the crystal of the present invention is preferred as the active ingredient for the pharmaceutical preparation (medicament preparation) to be produced in accordance with the production method including the sterilizing filtration (sterilization filtration) step.
- the pharmaceutical preparation (medicament preparation) as described above can be preferably exemplified, for example, by injections (injectable medicines) which are directed to vaginitis and pneumonia. It is a matter of course that the characteristic as described above scarcely causes any inconvenience or disadvantage even when the crystal of the present invention is applied to any other pharmaceutical preparation (medicament preparation). Therefore, the crystal of the present invention can be used, for example, for therapeutic agents for trichophytosis. This feature may be further described as follows. That is, the treatment or process, in which fine or minute undissolved matters are removed by means of a pore size of 0.2 to 0.5 ⁇ m, is advantageous in order to improve the time-dependent stability as well. In view of the fact as described above, the crystal of the present invention can be used as an active pharmaceutical ingredient. This material is the active pharmaceutical ingredient of the present invention.
- the active pharmaceutical ingredient of the present invention can contain substances, impurities, and analogs within a range as permitted in relation to the active pharmaceutical ingredient, other than the crystal of luliconazole. However, it is especially preferable to adopt a form consisting essentially of the crystal of luliconazole.
- the diffraction peak represents the (011) plane. Two sulfur atoms are arranged on this plane.
- the crystal has such a crystal habit that the (11-1) plane is the specific crystal growth plane, wherein phenyl group is arranged on this plane.
- the pharmaceutical composition of the present invention is characterized in that the pharmaceutical composition contains the crystal of the present invention or the active pharmaceutical ingredient of the present invention described above.
- the crystal as described above is excellent in the solubility in lower alcohol such as ethanol or the like, wherein fine or minute crystals, which are hardly sensed by naked eyes, scarcely remain in the dissolving step.
- the fine crystals as described above are removed in the step of performing the filtration, especially the sterilizing filtration with a pore size of 0.2 ⁇ m to 0.5 ⁇ m.
- any fine crystal as described above does not remain. Therefore, it is possible to avoid the deterioration of the activity corresponding thereto.
- the activity which is deteriorated during the process as described above, does not substantially affect the data of MIC or the like.
- any delicate influence is exerted on the threshold value of the efficacy of the medicine. Therefore, it is preferable that the amount of deteriorated activity is small, in view of the purport of the medicine. Further, any remaining fine crystal may induce the crystallization in a time-dependent manner. Therefore, it is preferable that fine or minute crystals are removed in this sense as well.
- the crystal of the present invention or the active pharmaceutical ingredient of the present invention is useful as the active ingredient for the pharmaceutical preparation which has any possibility to cause the deterioration of the activity as described above, in other words, for the pharmaceutical preparation for which the step of performing the sterilizing filtration is included in the production steps.
- the content of luliconazole in the pharmaceutical composition of the present invention is preferably 0.1 to 30% by mass and more preferably 0.5 to 15% by mass with respect to the total amount of the pharmaceutical composition.
- the pharmaceutical preparation of the present invention can be produced by performing the process or treatment in accordance with any ordinary method while appropriately adding thereto, for example, solvent, coloring agent, antioxidant, chelating agent, emulsifier/dispersing agent, solubilizing agent, disintegrating agent, excipient, binding agent, coating agent, and taste/odor-correcting agent other than the luliconazole crystal having such a crystal habit that the (011) plane is the specific crystal growth plane.
- the pharmaceutical composition of the present invention is preferably used to treat or cure the disease caused by any fungus or prevent the deterioration of the disease by utilizing the characteristic of luliconazole.
- the disease caused by any fungus can be exemplified by tinea pedis such as athlete's foot, tinea corporis such as candidiasis and tinea versicolor , and trichophytosis of hard keratin portion such as tinea unguium . It is especially preferable to use the pharmaceutical composition of the present invention for treating the disease of the hard keratin portion such as tinea unguium , because the effect thereof is remarkable.
- the effect of the pharmaceutical composition of the present invention is expressed on the nail especially preferably.
- the pharmaceutical composition which is directed to the dermatomycosis and which fulfills the construction of the present invention, also belongs to the technical scope of the present invention.
- the dermatomycosis as described above can be exemplified, for example, by the tinea pedis and the trichophytosis of the propagation in horny substance type, the trichophytosis of the propagation in horny substance type appearing, for example, in the heel and being included in the tinea pedis .
- the dermatomycosis described above it is preferable to make the application to the trichophytosis of the propagation in horny substance type on which any ordinary agent or drug hardly exerts the effect, because the effect of the present invention remarkably arises. Further, it is also possible to preferably exemplify, for example, the application to vaginitis (colpitis) and pneumonia caused, for example, by Candida or Trichomonas , the percutaneous administration to outer labia, the intravaginal administration, the oral administration, and the administration by injection. In the case of the administration against Candida or Trichomonas as described above, it is possible to especially preferably exemplify the administration to outer labia.
- the mode of use can be appropriately selected while considering, for example, the body weight, the age, the sexuality, and the symptoms or condition of the patient.
- luliconazole is also used in accordance therewith.
- any preparation for external use it is possible to exemplify the application in an appropriate amount to the disease portion once or several times a day. It is preferable that the treatment as described above is performed every day. In the case of any internal medicine (agent), it is preferable to administer 500 mg to 2000 mg once or several times a day. In the case of any vaginal tablet, it is preferable to perform the adjustment so that the amount of luliconazole is 500 to 1500 mg and perform the administration intravaginally once per a day or several days. In the vaginal administration of luliconazole, it is possible to simultaneously treat protozoa such as Trichomonas and fungi such as Candida , which is preferred.
- protozoa such as Trichomonas
- fungi such as Candida
- the treatment can be performed by using one agent, which is preferred.
- vaginitis coldis caused by the simple infection of Trichomonas
- the effect of the present invention is exerted even when the target microorganism is any fungus. Therefore, the rights or claims of the crystal having the crystal habit and the pharmaceutical composition containing the concerning crystal as the active ingredient of the present invention also encompass the use as the antifungal agent to treat or prevent the simultaneous infection (coinfection) with protozoa as described above.
- the pharmaceutical composition of the present invention has the preventive effect.
- the powder X-ray diffraction measurement was performed under the following condition: apparatus: XRD-DSCII produced by Rigaku Corporation, Condition: X-ray source: CuK ⁇ , measurement temperature: room temperature, tube voltage: 40 kV, tube current: 40 mA, 2 ⁇ : 5 to 35°, step angle: 0.05°.
- apparatus XRD-DSCII produced by Rigaku Corporation
- X-ray source CuK ⁇
- measurement temperature room temperature
- tube voltage 40 kV
- tube current 40 mA
- 2 ⁇ 5 to 35°
- step angle 0.05°.
- Characteristic values obtained by the single crystal X-ray structure analysis were provided as shown in ⁇ Single crystal X-ray structure analysis data> described later on.
- the single crystal X-ray structure analysis was performed under the following condition: apparatus: RU-H2R produced by Rigaku Corporation, Condition: X-ray source: CuK ⁇ , measurement temperature: 26° C., tube voltage: 50 kV, tube current: 180 mA, 2 ⁇ max: 150.0°, structure analysis method: direct method (SHELX 86). Further, various pieces of data of the single crystal X-ray structure analysis, and the peak area ratio of the (11-1) plane and the peak area ratio of the (011) plane in the powder X-ray diffraction pattern are shown in ⁇ Integrated intensity ratio in powder X-ray diffraction measurement> described later on.
- FIG. 2 shows the crystal structure and the specific crystal growth plane as determined by means of the calculation (name of software: Mercury) from analysis values obtained according to the single crystal X-ray structure analysis.
- I (011) with respect to the sum total of I (001) , I (100) , I (10-1) , I (011) , I (110) , I (11-1) , I (10-2) , I (11-2) , I (020) , I (021) , I (20-2) , I (121) , I (013) , I (11-3) , and I (221) was 54%, and I (11-1) with respect to the same sum total was 2%, provided that integrated intensities of diffraction peaks, which corresponded to the (001), (100), (10-1), (011), (110), (11-1), (10-2), (11-2), (020), (021), (20-2), (121), (013), (11-3), and (221) planes, were designated as I (001) , I (100) , I (10-1) , I (011) , I (110) , I (11-1) , I (10-2) , I (11-2) , I (020) , I (021) , I (20
- Characteristic values obtained by the single crystal X-ray structure analysis were as follows. Further, various pieces of data of the single crystal X-ray structure analysis, and the peak area ratio of the (11-1) plane and the peak area ratio of the (011) plane in the powder X-ray diffraction pattern are shown below.
- Example 1 The powder X-ray diffraction measurement and the single crystal X-ray structure analysis were performed in the same manner as in Example 1.
- I (011) with respect to the sum total of I (001) , I (100) , I (10-1) , I (011) , I (110) , I (11-1) , I (10-2) , I (11-2) , I (020) , I (021) , I (20-2) , I (121) , I (013) , I (11-3) , and I (221) was 26%, and I (11-1) with respect to the same sum total was 5%, provided that integrated intensities of diffraction peaks, which corresponded to the (001), (100), (10-1), (011), (110), (11-1), (10-2), (11-2), (020), (021), (20-2), (121), (013), (11-3), and (221) planes, were designated as I (001) , I (100) , I (10-1) , I (011) , I (110) , I (11-1) , I (10-2) , I (11-2) , I (020) , I (021) , I (20
- Trichomonas vaginalis (clinically isolated strain) of the crystal was investigated while being compared with a crystal having such a crystal habit that the (11-1) plane was the specific crystal growth plane.
- a solution of 10% ethanol/physiological saline was used as a control.
- Crystal of Comparative Example described above was used as the crystal which had such a crystal habit that the (11-1) plane was the specific crystal growth plane.
- Crystal 2 was used as the crystal which had such a crystal habit that the (011) plane was the specific crystal growth plane.
- Each of the crystals of luliconazole was weighed in an amount of 7.02 mg to which 10 mL of ethanol was added to dissolve the crystal. After confirming the absence of the crystal by visual observation, 100 ⁇ L of the solution was used as an aliquot, and 900 ⁇ L of physiological saline was added thereto. The resultant solution was subjected to the sterilizing filtration by using a filter having a pore size of 0.22 ⁇ m to provide a sample of 5.02 ⁇ g/mL (final concentration). 250 ⁇ L of an aliquot was taken therefrom, to which 250 ⁇ L of 10% ethanol/physiological saline was added to provide a sample of 2.51 ⁇ g/mL (final concentration).
- Trichomonas medium F produced by Fuji Pharma Co., Ltd.
- 100 ⁇ L of Trichomonas culture (5 ⁇ 10 3 individuals of Trichomonas ) was added thereto, followed by being cultured for 96 hours. After performing cooling for 10 minutes in ice water, the medium was stirred, which was spread on a hemocytometer to count a number of survived individuals of Trichomonas .
- 0.5 mL of 10% ethanol/physiological saline was added in place of the sample. Results are shown in Table 1.
- An external preparation for skin was manufactured in accordance with the following formulation. That is, formulation components A and B were heated, stirred, and solubilized. After that, the component B was added to the components A, followed by being neutralized, stirred, and cooled. Sterilizing filtration was performed by using a filter having a pore size of 0.32 ⁇ m. This preparation is useful to cure or treat tinea pedis , candidiasis of outer labia, and trichomoniasis of outer labia.
- the present invention can be applied to the pharmaceutical.
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